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Pembrolizumab Expanded for First-Line Treatment of NSCLC

The FDA has approved an expanded label for pembrolizumab, an anti-PD-1 therapy, as monotherapy for the first-line treatment of patients with stage III non-small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 (tumor proportion score [TPS] >=1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

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The approval is based on results from the phase III KEYNOTE-042 trial in which overall survival (OS) was sequentially tested as part of a pre-specified analysis plan. In the trial, pembrolizumab monotherapy demonstrated a statistically significant improvement in OS compared with chemotherapy alone in patients whose tumors expressed PD-L1 with a TPS >=50 percent, with a TPS >=20 percent, and then in the entire study population (TPS >=1%).


The study enrolled 1,274 patients who were randomized (1:1) to receive pembrolizumab 200 mg intravenously every 3 weeks (n=637) or investigator's choice of either of the following chemotherapy regimens (n=637):


* pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5-6 mg/mL/min every 3 weeks on day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; or


* paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5-6 mg/mL/min every 3 weeks on day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies.



The results of all efficacy outcome measures in the subgroup of patients with PD-L1 TPS >=20 percent NSCLC were intermediate between the results of those with PD-L1 TPS >=1 percent and those with PD-L1 TPS >=50 percent. In a pre-specified exploratory subgroup analysis for patients with TPS 1-49 percent NSCLC, the median OS was 13.4 months (95% CI, 10.7-18.2) for the pembrolizumab group and 12.1 months (95% CI, 11.0-14.0) in the chemotherapy group, with an HR of 0.92 (95% CI, 0.77-1.11).


In KEYNOTE-042, the safety of pembrolizumab was investigated in patients with PD-L1 expression, previously untreated stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC. Pembrolizumab was discontinued for adverse reactions in 19 percent of 636 patients. The most common adverse reactions resulting in permanent discontinuation of pembrolizumab were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%).


"The KEYNOTE-042 trial demonstrated a survival benefit with [pembrolizumab] monotherapy across histologies in certain patients with stage III or metastatic non-small cell lung cancer whose tumors expressed PD-L1 in at least 1 percent of tumor cells," said Gilberto Lopes, MD, Associate Director for Global Oncology at the Sylvester Comprehensive Cancer Center at the University of Miami.


Allowance of Investigational New Drug Application Granted for CG-806

The FDA has completed their review of the Investigational New Drug (IND) submission for CG-806 and has granted IND allowance to initiate a clinical trial. It is a phase I, multicenter, open-label, dose-escalation study with expansions to assess the safety, tolerability, PK, and preliminary efficacy of CG-806 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphoma (NHL).


The trial will be conducted with orally administered CG-806 in patients with relapsed or refractory B-cell malignancies, including CLL/SLL and NHL, who have failed or are intolerant to standard therapies. The trial is expected to initiate in the second quarter of 2019.


Pending collection and careful review of the initial safety data and predictive pharmacokinetic data in humans from this trial, there are plans to seek allowance from the FDA to move into patient populations that include relapsed or refractory acute myeloid leukemia (AML) and myelodysplastic syndromes in a separate phase I trial.


CG-806 is an oral, first-in-class pan-FLT3/pan-BTK multi-cluster kinase inhibitor. This small molecule demonstrates potent inhibition of wild type and all mutant forms of FLT3 (including internal tandem duplication and mutations of the receptor tyrosine kinase domain and gatekeeper region), cures animals of AML tumors in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with AML.


Likewise, CG-806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser (C481S) mutant forms of the BTK enzyme, as well as other oncogenic kinase pathways operative in B-cell malignancies, suggesting CG-806 may be developed for various B-cell malignancy patients (including CLL/SLL, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and others) that are resistant/refractory/intolerant to covalent BTK inhibitors. Because CG-806 targets key kinases/pathways operative in malignancies derived from the bone marrow, it is in development for B-cell cancers and AML.


First Targeted Therapy Approved for Metastatic Bladder Cancer

The FDA granted accelerated approval to erdafitinib, a treatment for adult patients with locally advanced or metastatic bladder cancer that has a type of susceptible genetic alteration known as FGFR3 or FGFR2, and that has progressed during or following prior platinum-containing chemotherapy. Patients should be selected for therapy with erdafitinib using an FDA-approved companion diagnostic device.


"We're in an era of more personalized or precision medicine, and the ability to target cancer treatment to a patient's specific genetic mutation or biomarker is becoming the standard, with advances being made in new disease types. [This] approval represents the first personalized treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "FGFRs regulate important biological processes including cell growth and division during development and tissue repair. This drug works by targeting genetic alterations in FGFRs."


The efficacy of erdafitinib was studied in a clinical trial that included 87 patients with locally advanced or metastatic bladder cancer, with FGFR3 or FGFR2 genetic alterations, that had progressed following treatment with chemotherapy. The overall response rate in these patients was 32.2 percent, with 2.3 percent having a complete response and almost 30 percent having a partial response. The response lasted for an average of approximately 5.5 months. About a quarter of patients in the study were previously treated with anti PD-L1/PD-1 therapy. Responses to erdafitinib were seen in patients who had previously not responded to anti PD-L1/PD-1 therapy.


Common side effects reported by patients taking erdafitinib were increased phosphate level, mouth sores, fatigue, change in kidney function, diarrhea, dry mouth, nails separating from the bed or poor formation of the nail, change in liver function, low sodium levels, decreased appetite, change in sense of taste, anemia, dry skin, dry eyes, and hair loss. Other side effects included redness, hand foot syndrome, constipation, stomach pain, nausea, and muscle pain.


Erdafitinib received accelerated approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need using clinical trial data that is thought to predict a clinical benefit to patients. Further clinical trials are required to confirm erdafitinib's clinical benefit and the sponsor is conducting or plans to conduct these studies. It was also granted Breakthrough Therapy designation.


The FDA also approved the therascreen FGFR RGQ RT-PCR Kit for use as a companion diagnostic with erdafitinib for this therapeutic indication.